Chronic caffeine decreases anxiety-like behavior in the marble burying task in adolescent rats.

Exposure to chronic caffeine during adolescence has been shown to produce decreased anxiety-like behaviors in rats as well as decreased immobility in the forced swim test (FST) suggesting an antidepressant-like effect. The effects of chronic caffeine on anxiety, however, have been found to be test-dependent and sexually dimorphic. In addition, decreased immobility in the FST has been argued to reflect a shift toward active coping behavior as opposed to an antidepressant-like effect. In order to further characterize the effects of adolescent caffeine exposure, the present experiment assessed the effects of caffeine on marble burying behavior in a two-zone marble burying task. There was no difference in the amount of time rats spent in the two zones failing to support a shift in coping strategy. Caffeine-exposed rats spent less time engaged in marble burying activity and buried slightly fewer marbles, suggesting an anxiolytic effect of caffeine. In addition, caffeine treated rats spent less time engaged in nondirected burying and slightly more time actively engaging with the marbles; however, these effects appeared to be sexually dimorphic as they were driven by larger changes in the females. Overall, these results support an anxiolytic effect of adolescent caffeine, with female behavior appearing to be more affected by caffeine than males.

Methylphenidate Reversal of Dexmedetomidine-Induced Versus Ketamine-Induced Sedation in Rats.

BACKGROUND: Dexmedetomidine and ketamine have long elimination half-lives in humans and have no clinically approved reversal agents. Methylphenidate enhances dopaminergic and noradrenergic neurotransmission by inhibiting reuptake transporters for these arousal-promoting neurotransmitters. Previous studies in rats demonstrated that intravenous methylphenidate induces emergence from isoflurane and propofol general anesthesia. These 2 anesthetics are thought to act primarily through enhancement of inhibitory Gamma-aminobutyric acid type A (GABAA) receptors. In this study, we tested the behavioral and neurophysiological effects of methylphenidate in rats after low and high doses of dexmedetomidine (an alpha-2 adrenergic receptor agonist) and ketamine (an N-methyl-D-aspartate [NMDA] receptor antagonist) that induce sedation and unconsciousness, respectively. METHODS: All experiments used adult male and female Sprague-Dawley rats (n = 32 total) and all drugs were administered intravenously in a crossover, blinded experimental design. Locomotion after sedating doses of dexmedetomidine (10 µg/kg) or ketamine (10 mg/kg) with and without methylphenidate (5 mg/kg) was tested using the open field test (n = 16). Recovery of righting reflex after either high-dose dexmedetomidine (50 µg/kg) or high-dose ketamine (50 mg/kg) with and without methylphenidate (1-5 mg/kg) was assessed in a second cohort of rats (n = 8). Finally, in a third cohort of rats (n = 8), frontal electroencephalography (EEG) was recorded for spectral analysis under both low and high doses of dexmedetomidine and ketamine with and without methylphenidate. RESULTS: Low-dose dexmedetomidine reduced locomotion by 94% in rats. Methylphenidate restored locomotion after low-dose dexmedetomidine (rank difference = 88.5, 95% confidence interval [CI], 70.8-106) and the effect was blocked by coadministration with a dopamine D1 receptor antagonist (rank difference = 86.2, 95% CI, 68.6-104). Low-dose ketamine transiently attenuated mobility by 58% and was not improved with methylphenidate. Methylphenidate did not affect the return of righting reflex latency in rats after high-dose dexmedetomidine nor ketamine. Frontal EEG analysis revealed that methylphenidate reversed spectral changes induced by low-dose dexmedetomidine (F [8,87] = 3.27, P = .003) but produced only transient changes after high-dose dexmedetomidine. Methylphenidate did not induce spectral changes in the EEG after low- or high-dose ketamine. CONCLUSIONS: Methylphenidate reversed behavioral and neurophysiological correlates of sedation, but not unconsciousness, induced by dexmedetomidine. In contrast, methylphenidate did not affect sedation, unconsciousness, nor EEG signatures in rats after ketamine. These findings suggest that methylphenidate may be efficacious to reverse dexmedetomidine sedation in humans.

Nanostructural Uniformity of Ordered Mesoporous Materials: Governing Lithium Storage Behaviors.

Nanostructured materials make a considerable impact on the performance of lithium-storage characteristics in terms of the energy density, power density, and cycle life. Direct experimental observation, by a comparison of controlled nanostructural uniformity of electrode materials, reveals that the lithium-storage behaviors of mesoporous MoO2 and CuO electrodes are linearly correlated with their nanostructural uniformity. Reversible capacities of mesoporous MoO2 and CuO electrodes with well-developed nanostructures (1569 mA h g-1 for MoO2 and 1029 mA h g-1 for CuO) exceed their theoretical capacity based on the conversion reaction (838 mA h g-1 for MoO2 and 674 mA h g-1 for CuO). Given that exact understanding of the origin of the additional capacity is essential in maximizing the energy density of electrode material, this work may help to gain some insights into the development of high energy-density lithium-storage materials for next-generation lithium rechargeable batteries.

Optimization of Oligosaccharide Production from Leuconostoc lactis Using a Response Surface Methodology and the Immunostimulating Effects of These Oligosaccharides on Macrophage Cells.

Production of oligosaccharides from Leuconostoc lactis CCK940 was optimized using a response surface methodology with a central composite design. Culture temperature and the concentrations of sucrose and maltose were used as the main factors. The predicted optimum conditions for the production of oligosaccharides were a culture temperature of 30 °C, a sucrose concentration of 9.6% (w/v), and a maltose concentration of 7.4% (w/v). Using these optimal conditions, Leuconostoc lactis CCK940 was cultured using a fermenter to produce oligosaccharides, and the resulting oligosaccharides with a degree of polymerization greater than 4 were purified by Bio-gel P2 gel permeation column chromatography and then lyophilized. When macrophages were treated with the purified oligosaccharides at concentrations of 0.1⁻10 mg/mL, no cytotoxicity towards the macrophages was observed. However, nitric oxide production levels were similar to those following treatment with 1 µg/mL lipopolysaccharide. The mRNA expression levels of tumor necrosis factor-α, interleukin-1ß, interleukin-6, and inducible nitric oxide synthase were all also increased in a dose-dependent manner following treatment with the oligosaccharides. These data suggest that oligosaccharides produced by Leuconostoc lactis CCK940 could be used as an immune enhancer of macrophages.

2,4-Bis(1,1-dimethylethyl)phenol from Cinnamomum loureirii Improves Cognitive Deficit, Cholinergic Dysfunction, and Oxidative Damage in TMT-Treated Mice.

We previously reported that the extract of Cinnamomum loureirii (C. loureirii) significantly inhibited acetylcholinesterase (AChE), and identified 2,4-bis(1,1-dimethylethyl)phenol (BP) from C. loureirii as a potential AChE inhibitor. The present study, therefore was undertaken to demonstrate the effects of BP from C. loureirii on learning and memory impairment in trimethyltin (TMT)-treated ICR mice. Y-maze and passive avoidance tests were used to test cognitive ability. Further, changes in biochemical parameters in the brain tissue were also assessed in response to TMT injection and BP intervention. BP pre-administration (20, 40 mg/kg/d) in mice significantly protected cognitive dysfunction induced by TMT (p<0.05). Moreover, BP reduced AChE activity and lipid peroxidation but increased acetylcholine levels in the brain. In conclusion, we suggested that BP protected against TMT-induced cognitive dysfunction, and might be a potential agent for alleviating symptoms of neurodegenerative disorders, such as Alzheimer's disease, via modulating cholinergic functions.

Semi-Continuous Fermentation of Onion Vinegar and Its Functional Properties.

For the fermentation of vinegar using onion, acetic acid bacteria and yeast strains with high fermentation ability were screened. Among them, Saccharomyces cerevisiae 1026 was selected as a starter for ethanol production and Acetobacter orientalis MAK88 was selected as a vinegar producer. When the two-stage fermentation of onion vinegar was performed at 28 °C, the titratable acidity reached 4.80% at 24 h of fermentation. When semi-continuous fermentation proceeded to charge-discharge consisting of three cycles, the acetic acid content reached 4.35% at 48 h of fermentation. At this stage, the fermentation efficiency, acetic acid productivity, and specific product formation rate were 76.71%, 17.73 g/(L·d), and 20.58 g/(g·h), respectively. The process in this study significantly reduced the fermentation time and simplified the vinegar production process. The content of total flavonoids and total polyphenols in onion vinegar were 104.36 and 455.41 µg/mL, respectively. The antioxidant activities of onion vinegar in terms of 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic) acid (ABTS⁺) radical scavenging activity, and reducing power were 75.33%, 98.88%, and 1.28, respectively. The nitrite scavenging abilities of onion vinegar were 95.38 at pH 1.2. The onion vinegar produced in this study showed higher organoleptic acceptability than commercial onion vinegar.

Cinnamomum loureirii Extract Inhibits Acetylcholinesterase Activity and Ameliorates Trimethyltin-Induced Cognitive Dysfunction in Mice.

The pathogenesis of Alzheimer's disease (AD) has been linked to the deficiency of neurotransmitter acetylcholine (ACh) in the brain, and the main treatment strategy for improving AD symptoms is the inhibition of acetylcholinesterase (AChE) activity. In the present study, we aimed to identify potent AChE inhibitors from Cinnamomum loureirii extract via bioassay-guided fractionation. We demonstrated that the most potent AChE inhibitor present in the C. loureirii extract was 2,4-bis(1,1-dimethylethyl)phenol. To confirm the antiamnesic effects of the ethanol extract of C. loureirii, mice were intraperitoneally injected with the neurotoxin trimethyltin (2.5 mg/kg) to induce cognitive dysfunction, and performance in the Y-maze and passive avoidance tests was assessed. Treatment with C. loureirii extract significantly improved performance in both behavioral tests, suggesting that this extract may be neuroprotective and therefore beneficial in preventing or ameliorating the degenerative processes of AD, potentially by restoring cholinergic function.

Synthesis of Ordered Mesoporous Manganese Oxides with Various Oxidation States.

Ordered mesoporous MnO, MnO4, Mn2O3 and MnO2 materials with 3-D pore structure were suc- cessfully synthesized via a nano-replication method by using ordered mesoporous silica, KIT-6 (Cubic Ia3d space group mesostructure) as the template under specific oxidation and reduction conditions. Notably, ordered mesoporous MnO with a crystalline wall (rock salt structure) was syn- thesized for the first time, to the best of our knowledge. The synthesis of the ordered mesoporous MnO was achieved by reducing the ordered mesoporous Mn3O4 under an H2 atmosphere, while preserving the ordered mesostructure and crystalline wall throughout the solid/solid transformation. All of the ordered mesoporous manganese oxides with different crystal structures and oxidation states demonstrated almost the same spherical-like morphology with several hundred nanometers of particles. The synthesized ordered mesoporous manganese oxides had uniform dual mesopores (2-3 nm, and ~20 nm) and crystalline frameworks with large surface areas (86-140 m2/g) and pore volumes (0.27-0.33 cm3/g).

Effect of Chaenomeles sinensis Extract on Choline Acetyltransferase Activity and Trimethyltin-Induced Learning and Memory Impairment in Mice.

The aim of this study was to search for a novel choline acetyltransferase (ChAT) activator from plants traditionally grown in Korea. An ethanol extract from Chaenomeles sinensis Koehne showed the highest ChAT-activating effect in vitro in an assay that used human neuroblastoma cells and [(14)C]acetyl-CoA. The active compound was speculated to be stearic acid methyl ester (SAME). In an in vivo experiment, C. sinensis extract and SAME improved trimethyltin (TMT)-induced deficits in learning and memory in mice as assessed by a Y-maze behavioral test and a passive avoidance test. The C. sinensis extract might attenuate the TMT-induced brain disorder. This study suggests that SAME from C. sinensis might be useful in the treatment of Alzheimer's disease.

Detection of choline and phosphatidic acid (PA) catalyzed by phospholipase D (PLD) using MALDI-QIT-TOF/MS with 9-aminoacridine matrix.

Phospholipase D (PLD) catalyzes the hydrolysis of phosphatidylcholine (PC), the most abundant phospholipids of plasma membrane, resulting in the production of choline and phosphatidic acid (PA). Choline is a precursor of the neurotransmitter acetylcholine, whereas PA functions as an intracellular lipid mediator of diverse biological functions. For assessing PLD activity in vitro, PLD-derived choline has been often analyzed with radioactive or non-radioactive methods. In this study, we have developed a new method for detecting choline and PA with MALDI-QIT-TOF/MS by using 9-aminoacridine as a matrix. The standard calibration curves showed that choline and PA could be detected with linearity over the range from 0.05 and 1 pmol, respectively. Importantly, this method enables the concomitant detection of choline and PA as a reaction product of PC hydrolysis by PLD2 proteins. Thus, our simple and direct method would be useful to characterize the enzymatic properties of PLD, thereby providing insight into mechanisms of PLD activation.

Electrical stimulation of the ventral tegmental area restores consciousness from sevoflurane-, dexmedetomidine-, and fentanyl-induced unconsciousness in rats.

BACKGROUND: Dopaminergic neurons in the ventral tegmental area (VTA) are crucially involved in regulating arousal, making them a potential target for reversing general anesthesia. Electrical deep brain stimulation (DBS) of the VTA restores consciousness in animals anesthetized with drugs that primarily enhance GABAA receptors. However, it is unknown if VTA DBS restores consciousness in animals anesthetized with drugs that target other receptors. OBJECTIVE: To evaluate the efficacy of VTA DBS in restoring consciousness after exposure to four anesthetics with distinct receptor targets. METHODS: Sixteen adult Sprague-Dawley rats (8 female, 8 male) with bipolar electrodes implanted in the VTA were exposed to dexmedetomidine, fentanyl, ketamine, or sevoflurane to produce loss of righting, a proxy for unconsciousness. After receiving the dopamine D1 receptor antagonist, SCH-23390, or saline (vehicle), DBS was initiated at 30 µA and increased by 10 µA until reaching a maximum of 100 µA. The current that evoked behavioral arousal and restored righting was recorded for each anesthetic and compared across drug (saline/SCH-23390) condition. Electroencephalogram, heart rate and pulse oximetry were recorded continuously. RESULTS: VTA DBS restored righting after sevoflurane, dexmedetomidine, and fentanyl-induced unconsciousness, but not ketamine-induced unconsciousness. D1 receptor antagonism diminished the efficacy of VTA stimulation following sevoflurane and fentanyl, but not dexmedetomidine. CONCLUSIONS: Electrical DBS of the VTA restores consciousness in animals anesthetized with mechanistically distinct drugs, excluding ketamine. The involvement of the D1 receptor in mediating this effect is anesthetic-specific.

Unveiling the role of micropores in porous carbon for Li-S batteries using operando SAXS.

The movement of the sulfur species of a lithium-sulfur battery cathode was directly observed through pioneering operando SAXS analysis. Micropore is a prior repository for sulfur before and after the electrochemical reaction. Mesopore is actual reaction site for sulfur species. The separate properties of the pores were established, adding critical insight to advanced carbon cathode material design.

The tetramer structure of the glycoside hydrolase family 27 alpha-galactosidase I from Umbelopsis vinacea.

The crystal structure of Umbelopsis vinacea alpha-galactosidase I, which belongs to glycoside hydrolase family 27, was determined at 2.0 A resolution. The monomer structure was well conserved with those of glycoside hydrolase family 27 enzymes. The biological tetramer structure of this enzyme was constructed by the crystallographic 4-fold symmetry, and tetramerization appeared to be caused by three inserted peptides that were involved in the tetramer interface. The quaternary structure indicated that the substrate specificity of this enzyme might be related to the tetramer formation. Three N-glycosylated sugar chains were observed, and their structures were found to be of the high-mannose type.

EWS is a substrate of type I protein arginine methyltransferase, PRMT8.

EWS, a pro-oncoprotein which is encoded by the Ewing sarcoma (EWS) gene, contains arginine-glycine-glycine repeats (RGG box) in its COOH-terminus. We previously found that the RGG box of EWS is a target for dimethylation catalyzed by protein arginine methyltransferases (PRMTs). Although it has been observed that arginine residues in EWS are dimethylated in vivo, the endogenous enzyme(s) responsible for this reaction have not been identified to date. In the present study, we determined that EWS was physically associated with PRMT8, the novel eighth member of the PRMT family, through the COOH-terminal region of EWS including RGG3 with the NH2-terminal region of PRMT8 encompassing the S-adenosyl-L-methionine binding domain, and that arginine residues in EWS were asymmetrically dimethylated by PRMT8 using amino acid analysis with thin-layer chromatography. These results suggested that EWS is a substrate for PRMT8, as efficient as for PRMT1.

Exceptional Lithium Storage in a Co(OH)2 Anode: Hydride Formation.

Current lithium ion battery technology is tied in with conventional reaction mechanisms such as insertion, conversion, and alloying reactions even though most future applications like EVs demand much higher energy densities than current ones. Exploring the exceptional reaction mechanism and related electrode materials can be critical for pushing current battery technology to a next level. Here, we introduce an exceptional reaction with a Co(OH)2 material which exhibits an initial charge capacity of 1112 mAh g-1, about twice its theoretical value based on known conventional conversion reaction, and retains its first cycle capacity after 30 cycles. The combined results of synchrotron X-ray diffraction and X-ray absorption spectroscopy indicate that nanosized Co metal particles and LiOH are generated by conversion reaction at high voltages, and Co xH y, Li2O, and LiH are subsequently formed by hydride reaction between Co metal, LiOH, and other lithium species at low voltages, resulting in a anomalously high capacity beyond the theoretical capacity of Co(OH)2. This is further corroborated by AIMD simulations, localized STEM, and XPS. These findings will provide not only further understanding of exceptional lithium storage of recent nanostructured materials but also valuable guidance to develop advanced electrode materials with high energy density for next-generation batteries.

Visible-light-induced installation of oxyfluoroalkyl groups.

(Hetero)aryloxytetrafluoroethylation of heteroaromatics and alkenes has been achieved by visible-light photocatalysis utilizing readily synthesized oxyfluoroalkyl reagents. The mild reaction conditions and the high diversity on both substrates and oxyfluoroalkyl reagents make this a useful method for late-stage modifications in the development of various functional molecules.

Root extract of water dropwort, Oenanthe javanica (Blume) DC, induces protein and gene expression of phase I carcinogen-metabolizing enzymes in HepG2 cells.

BACKGROUND: Cytochrome P450 (CYP) isoenzymes are an important phase I enzyme system. In the present study, we investigated the effects of Oenanthe javanica (Blume) DC on CYP1A1 and CYP1A2. FINDINGS: Whole plants were completely dried and then divided into leaves, stems, and roots for extraction. The human liver hepatocellular carcinoma cell line HepG2 was treated with ethanol extracts of these organs for 72 h and mRNA and protein expression levels were assessed. The root extract of O. javanica significantly elevated the expression of both CYP1A1 and CYP1A2 mRNAs (by 68 and 102 %, respectively). Similarly, the CYP1A1 and CYP1A2 protein levels were increased by the root extract (by 112 and 157 %, respectively). The effects of the root extract were much more pronounced than those of leaf and stem extracts. Subsequent GC-MS analysis revealed that the levels of major coumarin derivatives, xanthotoxin, bergapten, and isopimpinellin, were significantly higher in O. javanica root extracts than in leaf or stem extracts. Of note, 5 µM xanthotoxin (the most abundant furanocoumarin in O. javanica) induced the expression of CYP1A1 mRNA as well as CYP1A2 mRNA and protein, albeit the CYP1A1 protein level was elevated only at 10 µM xanthotoxin. CONCLUSIONS: Although it is difficult to extrapolate such effects to metabolic outcomes because of the inherent limitations of in vitro experiments, it is important to note that dietary exposure to O. javanica may modulate phase I enzymes and thereby affect various xenobiotic metabolism.

Perilla frutescens Extract Ameliorates Acetylcholinesterase and Trimethyltin Chloride-Induced Neurotoxicity.

One of the critical features of Alzheimer's disease is cognitive dysfunction, which is, in part, due to decreases in acetylcholine (ACh). The ethanol extract of Perilla frutescens was selected for isolating the acetylcholinesterase (AChE) inhibitor based on preliminary screening. In vivo behavioral tests were performed to examine the effects of the P. frutescens extract on trimethyltin chloride-induced impairment of learning and memory in mice. A diet containing P. frutescens extract effectively reversed learning and memory impairment on the Y-maze and passive avoidance tests. To isolate the active compound from the P. frutescens extract, solvent partitioning, silica gel open column chromatography, thin-layer chromatography, and high-performance liquid chromatography were used. The AChE inhibitor was identified as rosmarinic acid.

Discovery of abnormal lithium-storage sites in molybdenum dioxide electrodes.

Developing electrode materials with high-energy densities is important for the development of lithium-ion batteries. Here, we demonstrate a mesoporous molybdenum dioxide material with abnormal lithium-storage sites, which exhibits a discharge capacity of 1,814 mAh g(-1) for the first cycle, more than twice its theoretical value, and maintains its initial capacity after 50 cycles. Contrary to previous reports, we find that a mechanism for the high and reversible lithium-storage capacity of the mesoporous molybdenum dioxide electrode is not based on a conversion reaction. Insight into the electrochemical results, obtained by in situ X-ray absorption, scanning transmission electron microscopy analysis combined with electron energy loss spectroscopy and computational modelling indicates that the nanoscale pore engineering of this transition metal oxide enables an unexpected electrochemical mass storage reaction mechanism, and may provide a strategy for the design of cation storage materials for battery systems.

Direct adaptive controller for nonaffine nonlinear systems using self-structuring neural networks.

A direct adaptive state-feedback controller is proposed for highly nonlinear systems. We consider uncertain or ill-defined nonaffine nonlinear systems and employ a neural network (NN) with flexible structure, i.e., an online variation of the number of neurons. The NN approximates and adaptively cancels an unknown plant nonlinearity. A control law and adaptive laws for the weights in the hidden layer and output layer of the NN are established so that the whole closed-loop system is stable in the sense of Lyapunov. Moreover, the tracking error is guaranteed to be uniformly asymptotically stable (UAS) rather than uniformly ultimately bounded (UUB) with the aid of an additional robustifying control term. The proposed control algorithm is relatively simple and requires no restrictive conditions on the design constants for the stability. The efficiency of the proposed scheme is shown through the simulation of a simple nonaffine nonlinear system.